王蕾 卜星彭 刘宇 吕吉元 张明升
联合抗氧化剂降压对自发性高血压大鼠脂代谢的影响
王蕾1卜星彭1刘宇2吕吉元3张明升2
目的 联合抗氧化剂牛磺酸与美托洛尔降压对自发性高血压大鼠(SHR)脂代谢的影响。方法 对SHR经美托洛尔(M)与牛磺酸(T)治疗2周,测定给药前后SHR血清总胆固醇(TC)、低密度脂蛋白胆固醇(L-DLC)、甘油三酯(TG),血浆ox-LDL,血清NO的含量。结果 (1)给药后M组SHR血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDLC)以及甘油三酯(TG)的含量均升高,T组降低。(2)ox-LDL:T组可以明显降低血浆中ox-LDL的含量,由用药前(33.45±5.48)pg/dl降至(21.91±5.55)pg/dl(P<0.05),M组则由用药前(31.27±3.11)pg/dl升至(47.45±4.87)pg/dl(P <0.05),T+M组由用药前为(31.64±4.52)pg/dl增至(36.36±6.25)pg/dl (P>0.05)。(3)合用组使血清NO水平显著升高,用药前(18.64±11.00)μmol/L 升至(20.96±7.89)μmol/L(P<0.05)。结论 美托洛尔发挥降压作用同时可能发生脂代谢紊乱,联合抗氧化剂牛磺酸可发挥积极的调脂作用。
自发性高血压大鼠;抗氧化剂;牛磺酸;ox-LDL
美托洛尔作为β受体阻滞剂类降压药物已在临床广泛应用,但其在有效降压的同时可能导致机体糖脂代谢紊乱等副作用的发生。牛磺酸作为机体的非必需氨基酸具有广泛的生物学效应,具有抗胰岛素抵抗、抗氧化等功能[1-2]。本实验通过观察联用抗氧化剂与美托洛尔对自发性高血压大鼠(Spontaneously Hypertensive Rat,SHR)脂代谢的改变,旨在对牛磺酸的调脂作用机制作初步探讨。
1.1分组及给药
自发性高血压大鼠(SHR),16周龄,雄性,体重250~280 g ,24只,血压:176~190 mm Hg(购自北京维通利华)。随机分为4组:美托洛尔组(M),牛磺酸组(T),美托洛尔与牛磺酸组(M+T),对照组(S),每组6只。
M组:美托洛尔[100 mg/(kg·d)]灌胃(ig);T组:牛磺酸[200 mg/(kg·d)]腹腔注射(ip);M+T组:美托洛尔[100 mg/(kg·d)]灌胃及牛磺酸[200 mg/(kg·d)]腹腔注射;S组:空白对照组。等容积的生理盐水灌胃。给药时间均为每日17:00,1次/d,连续给药14 d。
1.2指标测定
1.2.1血脂含量 给药前后SHR血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDLC)以及甘油三脂(TG)的含量均按1995年中华医学检验学会推荐的方法测定。
1.2.2血浆ox-LDL含量 用抗鼠ox-LDL单克隆抗体酶联反应板的双单抗夹心ELISA法测定。
1.2.3血清NO含量 用硝酸还原酶法测定。
1.3统计学分析
2.1血脂
给药前后SHR血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDLC)以及甘油三脂(TG)的含量测定结果见表1,统计学分析结果表明M组给药后血清中TC、LDLC、TG含量均升高,T组均降低,T+M组均升高,但差异无统计学意义(P >0.05)。
2.2血浆ox-LDL含量
T组可以明显降低血浆中ox-LDL的含量,由用药前(33.45±51.48)pg/dl降至(21.91±5.55)pg/dl(P<0.05),M组则由用药前(31.27±3.11)pg/dl升至(47.45±4.87)pg/dl(P <0.05),两药合用(T+M)组由用药前为(31.64±4.52)pg/dl增至(36.36±6.25)pg/dl(P>0.05),而对照组(S)变化不明显,用药前为(30.54±4.77)pg/dl,用药后为(32.55±2.75)pg/dl(P >0.05),见表1。
2.3血清NO含量
T组NO值用药前(18.64±11.00)μmol/L 升至(20.96±7.89)μmol/L(P<0.05), 两药合用使血清NO水平显著升高,即T+M组NO由用药前的(15.74±3.98)μmol/L升至(19.44±4.25) μmol/L(P<0.01), SHR空白对照组无明显变化。见表2。
表1 SHR血浆ox-LDL含量的变化(pg/dl)
表2 SHR血清NO含量的变化(μmol/L)
临床试验表明降压药美托洛尔升高血清甘油三酯及胆固醇含量[3]。这种对脂代谢的不良影响可能部分抵消β受体阻断剂所带来的益处,降低抗高血压治疗的远期效果。牛磺酸作为机体的非必需氨基酸具有广泛的生物学效应,其抗氧化及抗胰岛素抵抗得到公认。本实验结果显示,SHR服用美托洛尔14 d后血胆固醇水平增加,这与文献报道[3]一致。与牛磺酸合用后使血胆固醇水平下降,血LDL-C有下降趋势,但无统计学意义,这可能与服药时间过短有关,延长服药时间是否能使LDL-C下降具有统计学意义,还有待进一步研究。此外,本实验结果还显示联合牛磺酸用药组ox-LDL含量明显降低。ox-LDL系沉积在血管壁中的血浆LDL在各种细胞、超氧阴离子、金属离子或其它致氧化因子等的作用下发生氧化修饰而形成。一旦LDL发生了氧化修饰,就不再被LDL受体识别,而是被巨噬细胞的清道夫受体所识别并摄取,导致胆固醇在巨噬细胞中沉积,形成泡沫细胞。该过程被认为是AS发生的关键性步骤。ox-LDL可诱导内皮细胞对多种炎症因子的表达,进而导致血管损伤[4-6]。近来在牛主动脉内皮细胞中克隆出内皮细胞ox-LDL受体LOX-1表达,LOX-1表达与血压密切相关,随SHR血压升高,主动脉LOX-1表达增加。牛磺酸可导致血浆ox-LDL水平下降源自于它的抗氧化特性,可能是通过抑制LOX-1表达,减少ox-LDL生成而发挥作用的,且牛磺酸抗氧化应力作用可以增加NO产生[7-8],改善eNOS表达,进而改善血管内皮功能,说明其在改善有脂质紊乱状态下的内皮功能是有益的。Abebew等[9]在观察牛磺酸对大鼠主动脉反应性影响的实验中也证实牛磺酸能特异性降低血管的收缩,这种效应部分经由血管内皮来调整。此外牛磺酸能有效降低TG及AI(TC-HDL)/HDL-C。研究也证明牛磺酸可以治疗脂质过氧化物反应,降低血清LDL/VLDL,升高HDL,防止内皮功能损伤,并通过改善单核细胞功能,阻止斑块形成。本研究表明牛磺酸在调节脂代谢中发挥积极作用,与美托洛尔合用能有效改善其导致的脂代谢紊乱。
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Effect of Combined Anti Oxidants on Lipid Metabolism in Spontaneously Hypertensive Rats
WANG Lei1BU Xingpeng1LIU Yu2LV Jiyuan3ZHANG Mingsheng21 Department of Geriatric Medicine, Shanxi Hospital, Taiyuan Shanxi 030032, China, 2 Department of Pharmacology, Shanxi Medical University,Taiyuan Shanxi 030032, China, 3 Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan Shanxi 030032, China
Objective To investigate the combination of taurine and metoprolol therapy on the lipometabolism of spontaneous hypertensive rat (SHR). Methods SHR were treated by the taurine and metoprolol therapy for 2 weeks, and the levels of serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), plasma oxidatively modified low-density lipoprotein (ox-LDL), serum NO were determined. Results (1) After administration, the serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) and triglyceride (TG) in the M group were all increased, and the T group was decreased in SHR group. (2) Group ox-LDL, significantly reduce the content of plasma ox-LDL in T group, from before treatment (33.45±5.48) pg/dl fell (21.91±5.55) pg/dl (P<0.05). In group M, from before treatment (31.27±3.11) pg/dl rose (47.45±4.87) pg/dl (P<0.05). T+M from before treatment to (31.64±4.52)pg/dl increased (36.36±6.25) pg/dl (P>0.05). (3) The serum NO level was signifcantly higher in the combination group, and (18.64±11.00) μmol/L before treatment (20.96±7.89) μmol/L (P<0.05). Conclusion These results suggest that the lipometabolism disturbance may be induced by metoprolol,taurine plays a positive role in lipometabolism.
Spontaneously hypertensive rats, Antioxidant, Taurine, ox-LDL
R544
A
1674-9308(2016)22-0210-03
10.3969/j.issn.1674-9308.2016.22.139
山西省留学回国人员择优资助项目(2014A027)
基金项目:山西省科技厅国际合作项目(2013081059)
1 山西大医院老年医学科,山西 太原 030032;2 山西医科大学药理教研室,山西 太原 030032;3 山西医科大学第一医院心内科,山西 太原 030032
王蕾,E-mail:wang_leicn@hotmail.com